NSAIDs Implicated in Female Infertility

Non-steroidal anti-inflammatory drugs trigger temporary but reversible reductions in female fertility, according to a recent study presented at the European League Against Rheumatism Annual Congress (EULAR 2015).

The study, led by Dr. Sami Salman of the Department of Rheumatology, University of Baghdad, included 39 women of WomanPainkillerschildbearing age who suffer from back pain. Participants were divided into four groups, and given one of four treatments; diclofenac (100 mg once daily), naproxen (500 mg twice daily), etoricoxib (90mg once daily), or placebo.

In all four groups, the patients took the assigned treatment for 10 days, beginning on Day 10 of their menstrual cycles. The investigators evaluated the women using ultrasound and blood tests prior treatment, and again on Day 20.

The study showed significant suppression of ovulation and of progesterone levels following exposure to all the NSAIDs evaluated. Diclofenac causing the greatest reduction in ovulation (93%). Naproxen and etoricoxib reduced ovulation by 75% and 72%, respectively.

Normally, progesterone production is triggered by ovulation and by the release of Luteinizing Hormone. A reduced progesterone level makes sense as an indicator that a woman has failed to ovulate.

Dr. Salman’s study, which has not yet been published, provides the first clear evidence of the mechanism (inhibition of ovulation) through which NSAIDs reduce fertility in women. The findings are most relevant and significant for women with chronic conditions such as Rheumatoid Arthritis (RA), for whom NSAIDs are commonly prescribed to control pain and inflammation.

Other Evidence Against NSAIDs

This is not the first study to link NSAIDs with reduced fertility. In 2000, a study in the journal, Rheumatology by Mendonca and colleagues at St. Thomas Hospital, UK, also implicated NSAIDs as a cause of reversible infertility (Mendonca LL, et al. Rheumatology (Oxford). 2000;39(8):880-2).

The paper presented case studies of 4 women, all suffering from severe arthritis, with a history of long-term NSAID use, and treatment for infertility. After being counseled to stop taking NSAIDs, they each became pregnant shortly after cessation of the drugs.

All four women had been on diclofenac, which was shown by Salman and colleagues to exert the greatest inhibition of ovulation. While Mendonca’s team did not fully understand the mechanism, they recognized the link between NSAID use and a reduced rated of conception.

Rheumatoid Arthritis, Fertility and NSAIDs

Women with RA have lower overall fertility rates and longer conception times than healthy women. This has been known for a long time.

Two fairly recent studies corroborate that observation, and attempt to explain it. Independent teams led by Provost and colleagues, and Clowse and colleagues reviewed data from cohorts of women with RA, in efforts to identify potential causes of impaired fertility.

The most likely factors were reduced sexual function and libido due to pain and fatigue, decreased rates of sexual intercourse, and patient choice. But both research groups also held that infertility must be considered. (Provost, et al, Current Opinion in Rheumatology , 2014 26(3), p308-314; Clowse, et al, Arthritis Care & Research, 2012 64(5), p668-674)

Provost speculated that medications –including NSAIDs--and their secondary effects on ovulation might play a role, but was unable to come up with conclusive evidence. The Salman study may be the key to understanding why these women are less fertile.

NSAIDS work through the inhibition of cyclooxygenase (COX), which reduces production of prostaglandins. It is true that prostaglandins mediate many steps of inflammation, but they also play important roles within the female reproductive system. They control ovulation, menstrual cycling, and even induction of labor. Disruption of prostaglandin production and function could be the mechanism through which NSAIDS inhibit ovulation.

Clinical Significance

While Salman’s study provides many answers, it also poses new questions: Would short-term, occasional, episodic use of NSAIDs have the same negative impact on ovulation as prolonged use? Will all classes of NSAIDs yield the same results?

Salman’s group evaluated 3 specific drugs, representing 3 distinct NSAID subclasses, and there were problems with all of them. Whether or not these results can be generalized to all NSAIDs, both over-the-counter and prescription, is unknown. But given that each of the three drugs induced some degree of ovulatory and/or progesterone suppression suggests that the wisest choice for a woman trying to conceive is complete avoidance of all of NSAIDs.

Further studies are needed to determine if shorter, less regular consumption of NSAIDs would yield similar ovulatory suppression, and if other NSAIDS produce similar results.

NSAID Use in the US

In 2012, Holistic Primary Care reported that,“Americans fill 70 million NSAID prescriptions yearly, and consume roughly 30 billion doses of over-the-counter NSAIDs. Between 20-30% of US adults take them daily.”

These drugs are very widely available over-the-counter and by prescription, and they are the most commonly used pain medications in adults in the US. The most commonly used over-the-counter NSAIDS are aspirin, ibuprofen, and naproxen (Aleve).  

NSAIDS have long been implicated in stomach upset and pain, and overuse can lead to hospitalization or death. It may be time to add infertility to the list of unintended side effects.

Sara McNulty holds a Master’s degree in Nutrition and Integrative Health from the Maryland University of Integrative Health. She is currently pursuing Certified Nutrition Specialist license.

REFERENCES

Clowse MEB, Chakravarty E, Costenbader KH, Chambers C, & Michaud K. Effects of infertility, pregnancy loss, and patient concerns on family size of women with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Care & Research. 2012; 64(5): 668–674. http://doi.org/10.1002/acr.21593

Goldman, E. Healing the NSAID Nation: Finding Safer Alternatives for Chronic Inflammation. Holistic Primary Care. 2012; 13(2). http://www.holisticprimarycare.net/topics/topics-a-g/chronic-disease/1338-healing-the-nsaid-nation-finding-safer-alternatives-for-chronic-inflammation

Mendonca LL, Khamashta MA, Nelson-Piercy C, Hunt BJ, & Hughes GR. Non-steroidal anti-inflammatory drugs as a possible cause for reversible infertility. Rheumatology (Oxford, England). 2000; 39(8): 880–882.http://rheumatology.oxfordjournals.org/content/39/8/880.long

Provost M, Eaton JL, & Clowse MEB. Fertility and infertility in rheumatoid arthritis. Current Opinion in Rheumatology. 2014; 26(3): 308–314. http://doi.org/10.1097/BOR.0000000000000058